Novel Computational Analysis Identifies Cytotoxic Lymphocyte-to-Monocyte Balance in Tumors as a Predictor of...

The microenvironment and immune infiltrate population of colorectal tumors can serve as a stronger predictor of patient survival than microsatellite-status or traditional T- or N-staging. This study aimed to leverage transcriptomic techniques to identify specific immune cell populations and their ratios associated with cancer recurrence in colorectal cancer patients. The goal was to identify patients who could benefit from early adjuvant interventions, identify those at higher risk of recurrence for surveillance, and identify potential combinatorial immunotherapy strategies tailored to this disease. We found that a lower ratio of cytotoxic lymphocyte: monocytic lineage cells, and not microsatellite-status, was associated with cancer recurrence. Additional differential gene expression analysis of the monocytic lineage demonstrated that genes specifically associated with tumor associated macrophages and a protumoral phenotype were overexpressed in the tumor microenvironment in patients that went on to have recurrent disease. Gene Ontology analysis revealed that pathways associated with pro-tumoral extracellular matrix remodeling were suppressed in tumors exhibiting a high cytotoxic lymphocyte: monocytic lineage ratio, suggesting a diminished propensity for tumor progression. The development of these prognostic markers not only associates with colorectal cancer recurrence, aiding in risk stratification and guiding adjuvant therapy decisions for resected early-stage patients, but also suggests that effective colon cancer treatments will likely require a combination of cytotoxic T-cell-directed immunomodulation and targeted inhibition of tumor-associated macrophages.